Inflammatory Bowel Disease. (IBD) is a chronic, relapsing inflammatory disorder of the GI tract. It is caused by inappropriate and chronic activation of the innate immune system in the gut. Patients show elevated levels of pro-inflammatory cytokines including IL-12, IL-18, TNFα, IFNγ, IL-2, IL-1, IL-6 and IL-8. The most common forms of IBD are Crohn's Disease (CD) and Ulcerative Colitis (UC). Symptoms associated with these conditions include abdominal pain, vomiting, diarrhea, rectal bleeding, severe internal pelvic cramps and weight loss. These symptoms can severely restrict quality of life. In addition, complications of the disease can lead to bowel rupture, bleeding from deep ulcerations, intestinal blockages and fistulae, secondary infections and increased risk of colon cancer.
Estimates suggest that the global prevalence rate of IBD is as much as 396 people per 100,000. In the USA IBD is one of the five most prevalent gastrointestinal disease burdens with as many as 1.4 million sufferers leading to healthcare costs of more than $1.7 billion. Each year in the United States, IBD accounts for more than 700,000 physician visits, 100,000 hospitalizations, and disability in 119,000 patients (Centre for Disease Control and Prevention website).
IBD is a chronic condition and there is no pharmacological cure. Patients usually require treatment for symptomatic relief throughout their lifetime and over the long term up to 75% of patients with Crohn's disease and 25% of those with ulcerative colitis will require surgery.
The aim of current treatment strategies is to induce remission after which the patient can be switched to a lighter treatment regime with fewer side effects until the next flare up occurs.
The drugs commonly used to induce remission and alleviate the symptoms of IBD are antiinflammatories (aminosalicylates (5-ASA, mesalazine), steroids, immunosuppressors (azathioprine, 6-MP, and methotrexate), antibiotics (metronidazole, ampicillin, ciprofloxin, others), and anti-TNF biologics (inflixamab, humira). Surgery becomes necessary when medications can no longer control the symptoms. Ulcerative colitis can be effectively cured after removal of the colon (colectomy), but Crohn's disease can recur after surgery.
Macrophages express Toll-Like Receptors (TLRs) that detect core components of pathogens, triggering the activation of signaling pathways that lead to the production of inflammatory mediators needed to combat infection1. However this defence system is a double-edged sword because failure to resolve inflammation can cause chronic inflammatory diseases and/or autoimmune disorders, such as rheumatoid arthritis and systemic lupus erythematosus1-3. Regulatory macrophages that produce high levels of anti-inflammatory molecules, such as interleukin (IL)-10, and low levels of pro-inflammatory cytokines, like IL-12, are thought to be crucial for the resolution of inflammatory responses4. A central problem in this area is therefore to understand how to promote the formation of regulatory macrophages at sites of inflammation.
SIKs (Salt Induced Kinases) are serine threonine kinases of the AMPK-related kinase family. SIK1 was first cloned in 1999 as a kinase that was upregulated in the adrenal glands of rats in response to a high salt diet (Wang et al, FEBS Lett 1999). Since then two other isoforms SIK2 and SIK3 have been identified. SIK1 is expressed at high levels in the adrenal gland and also in the brain, pituitary, ovary, testis and lung. SIK2 is expressed in white and brown adipose tissue and SIK3 is ubiquitous. SIK1 is best characterized as mediating repression of steroidogenic genes by inhibiting CRTC-CREB-dependent transcription. SIK2 is best characterized as regulating gluconeogenesis under conditions of fasting. Increases in circulating glucagon promote PKA-dependent inhibition of SIK2, which leads to CRTC2 activation and CRTC2-CREB dependent induction of gluconeogenesis genes. Normally SIK2 is maintained in an active state in response to insulin-AKT-dependent regulation.
The physiological role of SIK3(QSK) remains unclear although it may play a role in cell proliferation based on the finding that the drosophila KO shows spindle defects and chromosomal abnormalities (M. Bettencourt-Dias, R. Giet, R. Sinka, A. Mazumdar, W. G. Lock, F. Balloux, P. J. Zafiropoulos, S. Yamaguchi, S. Winter, R. W. Carthew, M. Cooper, D. Jones, L. Frenz & D. M. Glover Nature 432, 980-987 (2004) Genome-wide survey of protein kinases required for cell cycle)